The overall goal of medical research is to improve feeling, functioning and survival. Towards this aim, medical research attempts to assess causality. A target is a hypothesized mechanism of action which, if probed, modifies disease, as evidenced by behavioral and clinical outcome. The target must be associated with deficits in symptoms at baseline. Then, modifications of that target mediate symptom improvement. Our program probes neural and physiological deficits associated with illness; once identified, we leverage these deficits to develop novel targeted interventions. Our group has completed a randomized controlled trial (N=44, active vs. placebo) of a computer-based treatment engaging behavioral and neural targets of aberrant threat processing. In addition, we developed an analogous fMRI paradigm to probe neural correlates in a large (N>100) sample of youth with varying degrees of irritability. Leveraging computational modeling, we found unique neural correlates associated with latent factor-derived phenotype of high irritability and anxiety, previously validated in two independent clinical samples (Kircanski et al., 2018; Cardinale et al., 2019). We have also developed an exposure-based cognitive behavioral therapy with resting and task-based fMRI pre, mid and post-treatment. The fMRI tasks probe reward, threat, and frustration processing. N=20 youth have been randomized; recruitment continues to be robust. Moreover, we leverage technology to assess symptoms by utilizing digitally based event sampling (ecological momentary assessment). We have also developed a cognitive inhibition frustration mobile application with peripheral physiological measures (e.g., heart rate via apple watch). These interventions provide the foundation for scalable, target-based interventions which are more easily disseminated, facilitating public health impact. Finally, our translational perspective has been supported by a Bench-to-Bedside Award. We developed an fMRI paradigm; N=20 have completed the task. We have also developed an eye tracking study; N=30 have completed the task. Ultimately, these mechanistic studies will allow for more targeted interventions for pathological irritability.